This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Comparison of protein sequences from completely sequenced genomes allows the clustering of the amino acid sequences into related families. The structures of the protein members of a sequence family will all be similar. While determining the structures of all proteins is an unreasonable aim, the determination of one structure from each sequence family is an attainable goal and the aim of the NIH Protein Structure Initiative. The large scale sequencing and structure determination efforts are going to provide extensive background information and lead to the question: What are the biological roles of these proteins? Those that have homologues in many widely divergent species must play an important role under some conditions in order to have been so widely retained through evolution and they are likely to have related functions in these diverse organisms. The sequencing efforts thus point out important proteins that are relatively uncharacterized and that require further investigation if we are to utilize the sequence information to expand our understanding of biology. The next logical step is to determine the biochemical functions of such proteins. We are interested in using protein structure to aid computational and experimental approaches to identifying possible ligands for proteins of unknown, or poorly defined function.